Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury

Kaliyamurthi Venkatachalam, Sumanth D. Prabhu, Venkatapuram Seenu Reddy, William H. Boylston, Anthony J. Valente, Bysani Chandrasekar

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82 Scopus citations

Abstract

Ischemia/reperfusion (I/R) injury is characterized by the induction of oxidative stress and proinflammatory cytokine expression. Recently demonstrating that oxidative stress and TNF-α each stimulate interleukin (IL)-18 expression in cardiomyocytes, we hypothesized that I/ R also induces IL-18 expression and thus exacerbates inflammation and tissue damage. Neutralization of IL-18 signaling should therefore diminish tissue injury following I/R. I/R studies were performed using a chronically instrumented closed chest mouse model. Male C57BL/6 mice underwent 30 min of ischemia by LAD coronary artery ligation followed by various periods of reperfusion. Sham-operated or ischemia-only mice served as controls. A subset of animals was treated with IL-18-neutralizing antibodies 1 h prior to LAD ligation. Ischemic LV tissue was used for analysis. Our results demonstrate that, compared with sham operation and ischemia alone, I/R significantly increased (i) oxidative stress (increased MDA/4-HNE levels), (ii) neutrophil infiltration (increased MPO activity), (iii) NF-κB DNA binding activity (p50, p65), and (iv) increased expression of IL-18Rβ, but not IL-18Rα or IL-18BP transcripts. Administration of IL-18-neutralizing antibodies significantly reduced I/R injury measured by reduced infarct size (versus control IgG). In isolated adult mouse cardiomyocytes, simulated ischemia/reperfusion enhanced oxidative stress and biologically active IL-18 expression via IKK-dependent NF-κB activation. These results indicate that IL-18 plays a critical role in I/ R injury and thus represents a promising therapeutic target.

Original languageEnglish (US)
Pages (from-to)7853-7865
Number of pages13
JournalJournal of Biological Chemistry
Volume284
Issue number12
DOIs
StatePublished - Mar 20 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Venkatachalam, K., Prabhu, S. D., Reddy, V. S., Boylston, W. H., Valente, A. J., & Chandrasekar, B. (2009). Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury. Journal of Biological Chemistry, 284(12), 7853-7865. https://doi.org/10.1074/jbc.M808824200